Tiny Tweak to LSD Molecule Creates Powerful Treatment for Brain Disorders Without Hallucinations

Scientists have developed a promising new compound that could change how we treat conditions like schizophrenia by harnessing the therapeutic benefits of psychedelics without their hallucinogenic effects.

Researchers at the University of California Davis and San Diego have created JRT, a modified version of LSD that promotes neural growth and connectivity while eliminating the hallucinogenic properties that make traditional psychedelics unsuitable for patients with certain mental health conditions.

The breakthrough, published in the Proceedings of the National Academy of Sciences, hinged on a remarkably simple molecular modification—swapping the position of just two atoms in LSD’s structure.

“Basically, what we did here is a tire rotation,” said corresponding author David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics at UC Davis. By just transposing two atoms in LSD, we significantly improved JRT’s selectivity profile and reduced its hallucinogenic potential.

This subtle change maintained the compound’s ability to promote neural growth while eliminating the hallucinations that would make it dangerous for people with schizophrenia.

Using advanced 3D electron microscopy techniques, researchers observed remarkable neurobiological effects. A single dose of JRT increased dendritic spine density—key structures for neural connectivity—by 46% and synapse density by 18% in the prefrontal cortex of mice.

The implications for treating schizophrenia are particularly significant. Current medications for schizophrenia primarily address hallucinations and delusions but struggle to improve cognitive issues and emotional flatness (anhedonia).

No one really wants to give a hallucinogenic molecule like LSD to a patient with schizophrenia, noted Olson, who is also co-founder of Delix Therapeutics. The development of JRT emphasizes that we can use psychedelics like LSD as starting points to make better medicines—medicines that can be used in patient populations where psychedelic use is precluded.

Unlike existing treatments, JRT showed remarkable potency in animal models—approximately 100 times more potent than ketamine in antidepressant-like effects. The compound also demonstrated an ability to rescue cognitive flexibility in mice exposed to chronic stress without producing sedation or other problematic side effects associated with current antipsychotic medications.

The research represents a significant advance in the emerging field of “psychoplastogens”—compounds that promote neural plasticity without hallucinogenic effects. This approach could potentially address the underlying neurobiological deficits seen in schizophrenia, where decreased dendritic spine density and impaired connectivity in the cortex are hallmarks of the disease.

We are incredibly excited about the therapeutic potential of non-hallucinogenic psychedelic analogs like JRT, said Uri Manor, assistant professor at UC San Diego’s School of Biological Sciences. This work is a perfect example of how cutting-edge chemistry, neuroscience and imaging can come together to push the boundaries of biomedical research.

The development required significant chemical innovation. It took Olson’s team nearly five years to complete the 12-step synthesis process to produce JRT, named after Jeremy R. Tuck, the graduate student who first synthesized it.

The research team is now testing JRT’s potential against other neurodegenerative and neuropsychiatric diseases, highlighting the broader implications of this scientific approach—creating molecules that selectively target beneficial neural pathways while avoiding unwanted effects.

This research was supported by the National Institutes of Health, the UC Davis Provost’s Undergraduate Fellowship, the Camille and Henry Dreyfus Foundation, the Dr. Bhagwat Memorial Fund, the Hope for Depression Research Foundation, the Pritzker Neuropsychiatric Disorders Research Consortium, and the Chan Zuckerberg Initiative.